The implantation site during early human pregnancy is characterized by extensive remodeling of the vasculature, invasion of fetal trophoblast cells, and by an abundance of maternal NK cells. The remodeling of the maternal vasculature, which occurs over the first twelve weeks of pregnancy, is essential to establish sufficient blood supply to the fetus. How NK-trophoblast cell interactions influence vascular remodeling is unknown. Invading trophoblast cells from the fetus express the non-classical major histocompatibility class I molecule HLA-G. It was long thought that the role of HLA-G was to inhibit maternal NK cells, which would otherwise attack the fetus. However, our work has led to a radically different understanding of the function of NK cells in pregnancy. We have identified the killer cell immunoglobulin-like receptor (KIR) 2DL4 (KIR2DL4, also known as CD158d) as the receptor for HLA-G. KIR2DL4 binds soluble HLA-G and internalizes it into endosomal compartments inside NK cells. KIR2DL4 has the unique property of residing almost exclusively in endosomes. Endosomes have emerged recently as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses are still unclear. KIR2DL4 is an endosome-resident receptor in NK cells that stimulates the release of a unique set of proinflammatory and proangiogenic mediators in response to soluble HLA-G. Two major questions raised by these findings are the mechanisms for transport of KIR2DL4 to endosomes, and the signaling pathway triggered by KIR2DL4 once it is bound to soluble HLA-G within endosomes. We have identified the KIR2DL4 signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by KIR2DL4 was dependent on the activation of nuclear factor kB (NF-kB) and the serine-threonine kinase Akt. KIR2DL4 associated with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), promoted the recruitment of Akt to endosomes, and stimulated the DNA-PKcs dependent phosphorylation of Akt. The sequential requirement for DNA-PKcs, Akt, and NF-kB in signaling by KIR2DL4 delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in NK cells. We have further identified the molecular mechanism by which the KIR2DL4-mediated proinflammatory/proangiogenic response is initiated and sustained. This endosomal signaling pathway induced by soluble ligand drives NK cells to a senescent state where they neither proliferate nor undergo apoptosis. Instead, they are metabolically active and secrete mediators that promote angiogenesis and tissue remodeling. This has implications for NK cell function at sites of HLA-G expression such as vascular remodeling at the implantation site during early pregnancy and at the site of HLA-G expressing tumor cells.